Protein kinases are involved in signaling pathways for such important cellular activities as responses to extracellular signals and cell cycle checkpoints. Inhibition or activation of specific protein kinases provides a means of intervening in these signaling pathways, for example to block the effect of an extracellular signal, to release a cell from cell cycle checkpoint, etc. Defects in the activity of protein kinases are associated with a variety of pathological or clinical conditions, where there is a defect in the signaling mediated by protein kinases. Such conditions include those associated with defects in cell cycle regulation or in response to extracellular signals, e.g., immunological disorders, autoimmune and immunodeficiency diseases; hyperproliferative disorders, which may include psoriasis, arthritis, inflammation, endometriosis, scarring, cancer, etc.
Aberrant activation of the Ras-Raf-MAP kinase signaling pathway contributes to the process of tumorigenesis, i.e. the conversion of a normal into a malignant cell. Many molecular details have been worked out, how the MAPK signaling module initiates proliferation or inhibits apoptotic response, thus explaining how the homeostatic balance between proliferation and cell death can be disturbed. MKK1 and MKK2, also known as MEK1 and MEK2, represent a key element in this signaling cascade. MEKs are activated by Raf kinase phosphorylation and, in turn, phosphorylate and activate their bona fide substrates ERK1 and ERK2. Oncogenic Ras mutations, mutations in the effector kinase B-Raf and even growth factor overexpression and mutation may lead to persitant activation of the MAPK pathway justifying the potential of MAPK pathway inhibitors at a level of Raf, MEK or ERK as promising anticancer therapeutics.
Therefore, compounds, which are active in modulating purified kinase proteins, e.g. there is a modulation in the phosphorylation of a specific substrate in the presence of the compound, can be used for the treatment of protein kinase-dependent diseases and conditions, such as cancer, tumour growth, artherosclerosis, age-related macular degeneration, diabetic retinopathy, inflammatory diseases and the like, in mammals.
Amino-oxindoles are known from e.g. WO9952869, WO9962882, WO04026829, WO04009546, WO04009547, EP104860, U.S. Pat. No. 4,145,422, WO03027102 and WO0149287. 3-(1-Amino-2-phenyl-ethylidene)-1-methyl-1,3-dihydro-indol-2-one is known from Wenkert, E. et al., J. Am. Chem. Soc. (1958), 80, 4899-4903, 3-(Amino-phenyl-methylene)-1,3-dihydro-indol-2-one is known from Stauss, U. et al., Helv. Chim. Acta (1972), 55(3), 771-780.
Compounds described as putative MEK inhibitors are known from e.g. WO03062191, WO04056789, WO03077914, WO03077855, WO04041811 and WO04048386.
Thus, as there remains a need in advantageous therapeutics, a preferred object of the present invention was to provide new pharmaceutically active compounds. A particularly preferred aim of the present invention was to provide effective modulators of one or more protein kinases, especially selected from the group of Raf, MEK, PKB, Tie2, PDGFR, Met, SGK1, IGF1R and VEGFR.